Hu Yanmin, Liu Alexander, Vaudrey James, Vaiciunaite Brigita, Moigboi Christiana, McTavish Sharla M, Kearns Angela, Coates Anthony
Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
University of Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom.
PLoS One. 2015 Feb 18;10(2):e0117664. doi: 10.1371/journal.pone.0117664. eCollection 2015.
Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections.
细菌感染仍然是全球主要的致死原因，而抗生素耐药性的不断出现使这一情况更加恶化。特别是，甲氧西林敏感金黄色葡萄球菌（MSSA）和耐甲氧西林金黄色葡萄球菌（MRSA）很常见，后者可能难以治疗。新型治疗药物开发的传统策略不可避免地导致耐药菌株的出现，使新药失效。因此，恢复现有抗生素的治疗潜力提供了一种有吸引力的新策略。防御素抗菌肽plectasin可增强其他抗生素（如β-内酰胺类、氨基糖苷类和糖肽类）对MSSA和MRSA的活性。我们进行了体外和体内研究，以测试其对基因多样的MSSA临床分离株（n = 101）和MRSA临床分离株（n = 115）的效果。通过肉汤微量稀释法测定最低抑菌浓度（MIC）。使用棋盘法和时间杀菌曲线研究了plectasin与β-内酰胺类、氨基糖苷类和糖肽类联合使用的效果。使用小鼠中性粒细胞减少大腿模型和小鼠腹腔感染模型测试联合用药在体内的效果。通过分数抑菌浓度指数（FICI）测定，plectasin与氨基糖苷类（庆大霉素、新霉素或阿米卡星）联合使用在76 - 78%的MSSA和MRSA中显示出协同作用。当plectasin与β-内酰胺类（青霉素、阿莫西林或氟氯西林）联合使用时，在87 - 89%的MSSA和MRSA中观察到类似的协同反应。有趣的是，当plectasin与万古霉素配对时未观察到这种相互作用。时间杀菌分析也表明，当plectasin与阿莫西林、庆大霉素或新霉素联合使用时具有显著的协同活性。在小鼠模型中，低至8 mg/kg剂量的plectasin增强了阿莫西林和庆大霉素成功治疗MSSA和MRSA感染的活性。我们证明，plectasin在体外和体内均能显著恢复现有抗生素的治疗效力。这是一种新策略，在我们对抗细菌感染的斗争中可能具有重大临床意义。
